Methylation of leukocyte DNA and ovarian cancer: Relationships with disease status and outcome

Background: Genome-wide interrogation of DNA methylation (DNAm) in blood-derived leukocytes has become feasible with the advent of CpG genotyping arrays. In epithelial ovarian cancer (EOC), one report found substantial DNAm differences between cases and controls; however, many of these disease-associated CpGs were attributed to differences in white blood cell type distributions. Methods. We examined blood-based DNAm in 336 EOC cases and 398 controls; we included only high-quality CpG loci that did not show evidence of association with white blood cell type distributions to evaluate association with case status and overall survival. Results: Of 13,816 CpGs, no significant associations were observed with survival, although eight CpGs associated with survival at p < 10^-3, including methylation within a CpG island located in the promoter region of GABRE (p = 5.38 x 10^-5, HR = 0.95). In contrast, 53 CpG methylation sites were significantly associated with EOC risk (p <5 x10^-6). The top association was observed for the methylation probe cg04834572 located approximately 315 kb upstream of DUSP13 (p = 1.6 x10^-14). Other disease-associated CpGs included those near or within HHIP (cg14580567; p =5.6x10^-11), HDAC3 (cg10414058; p = 6.3x10^-12), and SCR (cg05498681; p = 4.8x10^-7). Conclusions: We have identified several CpGs in leukocytes that are differentially methylated by case-control status. Since a retrospective study design was used, we cannot differentiate whether DNAm was etiologic or resulting from EOC; thus, prospective studies of EOC-associated loci are the critical next step.